Nausea and Vomiting in Pregnancy

Without a doubt, nausea and vomiting are common side effects of pregnancy. “Morning sickness” is estimated to affect approximately 75% of all pregnant women. These symptoms typically begin around 5 to 6 weeks’ gestation, with the majority of patients experiencing resolution of symptoms by 16 weeks; only about 10% of patients will have persistence of nausea throughout pregnancy. Nausea and vomiting of pregnancy affects 50% to 90% of pregnant women and ranges from mild to moderate to the more severe hyperemesis gravidarum, which complicates 0.3% to 2% of pregnancies (1). Lacking a single uniform definition, hyperemesis gravidarum is a clinical diagnosis characterized by severe and intractable vomiting and is often associated with concomitant weight loss (defined as >5% of pre-pregnancy weight), ketonuria, dehydration, metabolic alkalosis, and electrolyte disturbances (2). More than its effect on quality of life, hyperemesis gravidarum can lead to severe medical complications. A step-wise approach involving non-pharmacologic and pharmacologic measures helps you and your patient to effectively manage pregnancy-related nausea. An appropriate index of suspicion and an organized approach to identification and therapy can help to ensure maximum benefit for both health care professional and patient.

The purpose of this document is to discuss appropriate diagnosis and management of hyperemesis gravidarum to improve the patient’s quality of life and provide best possible maternal and neonatal outcomes. Learning objectives are to differentiate hyperemesis gravidarum from ordinary “morning sickness” using diagnostic criteria, identify the maternal and fetal risks of hyperemesis gravidarum and propose treatment strategies for maintaining hydration and nutrition. The more common nausea and vomiting of pregnancy negatively affects the quality of life of pregnant women, decreases work productivity, and adversely affects family dynamics.

Hyperemesis Gravidarum

Epidemiology and Risk Factors
Hyperemesis gravidarum is the most common indication for hospitalization in the first half of pregnancy and second only to preterm labor as the most common reason for hospital admission in pregnancy, accounting for more than 39,000 hospital discharges and more than $500 million in hospital costs annually (3). It has a higher prevalence in the Western hemisphere in predominantly urban populations and is less common in African and Asian populations (4). Younger, primigravid women with less education also are at higher risk (4). Certain obstetric conditions, such as multiple gestation, trophoblastic disease, and fetal anomalies (trisomy 21, hydrops fetalis), are associated with an increased risk of hyperemesis gravidarum (4). Women with family history of hyperemesis, those with motion sickness or migraines, and those carrying females are at higher risk as well (5). A history of hyperemesis gravidarum in a prior pregnancy confers a 15% risk of recurring episode in a subsequent pregnancy, and the risk of recurrent nausea and vomiting of pregnancy is even higher (6). Comorbidities that may be of risk factors for hyperemesis gravidarum include hyperthyroid disorders, psychiatric illnesses, pre-gestational diabetes, gastrointestinal (GI) disorders, and asthma (7). Maternal smoking appears to be protective. Compared with dizygotic twin pairs, monozygotic twin mothers suffer from nausea and vomiting of pregnancy more often, arguing that maternal genetics may be the culprit (4).

Etiology

Hyperemesis gravidarum is characterized by persistent, severe nausea and vomiting. Although the exact pathogenesis of this condition is unknown, its etiology is likely multifactorial. Many theories have been proffered and include hormonal changes, psychological states, and evolutionary adaptation (8). Human chorionic gonadotropin (hCG) and its various isoforms have been implicated in the pathogenesis of nausea and vomiting of pregnancy (9). Serum hCG levels peak during the first trimester, and changes in its concentration mirror the clinical course of nausea and vomiting of pregnancy and hyperemesis gravidarum. The possible role of hCG is also supported by the observation that women with multiple gestations and molar pregnancies, conditions with higher hCG levels, are at higher risk.

Estrogen and progesterone have been considered to play a role in the development of nausea and vomiting of pregnancy and hyperemesis gravidarum (4),(9). Although unconfirmed, progesterone may be involved in altering gastric motility, which seems to correlate temporarily with symptoms of nausea and vomiting of pregnancy. Whereas older theories have proposed that nausea and vomiting of pregnancy may have a psychological predisposition and may represent an underlying psychosomatic illness or a woman’s altered response to stress, recent studies have not found such a link (4),(9). Another theory hypothesizes that nausea and vomiting of pregnancy developed as an evolutionary advantage to protect the mother and fetus from potential toxic foods, especially in the first trimester (9). The neuroanatomy of vomiting in humans has been well studied. A “vomiting center” exists in the dorso-lateral reticular formation of the medulla and the chemoreceptor trigger zone is located in the area postrema of the medulla oblongata. A signal travels along the afferent fibers of the vagus nerve to the chemoreceptor trigger zone, stimulating the vomiting center and triggering emesis.

Some data suggest that the prevalence of hyperemesis gravidarum varies by ethnic background. One study showed that women born in Western Europe had the lowest prevalence of hyperemesis gravidarum, whereas women born in India and Sri Lanka had the highest – a difference that could not be explained by socioeconomic factors (10). There also appears to be a high prevalence of severe nausea and vomiting among relatives of patients diagnosed with hyperemesis gravidarum, indicating a possible genetic component (5).

Clinical Features

Regardless of etiology, an organized approach can help expedite identification of the problem. Lacking a standard uniform definition, hyperemesis gravidarum is a clinical one of exclusion. Symptoms usually present at 5 to 6 weeks’ gestation, peak at 8 to 9 weeks’, and in 60% of cases, resolve by the end of the first trimester (11). However, 10% to 20% of women remain symptomatic during the third trimester. Contrary to the popular term “morning sickness”, 80% of women report symptoms occurring throughout the day. The clinical course of nausea and vomiting of pregnancy depends on the severity of symptoms, which range from mild nausea to hyperemesis gravidarum. Tools have been developed to quantify the severity of nausea and vomiting of pregnancy and to track its clinical course. The PUQE (pregnancy-unique quantification of emesis and nausea) scoring index includes the daily number of vomiting episodes, the length of nausea per day in hours, and the number of retching episodes (10). A modified PUQE score was developed to take into account nausea and vomiting occurring in the first trimester of pregnancy rather than in the previous day (11). Higher scores correlate with symptom severity and indicate which women require evaluation for dehydration and electrolyte abnormalities. These tools can be used to monitor the severity of symptoms.

In addition to eliciting the severity of nausea and vomiting, the patient history should aim to exclude alternative etiologies such as GI conditions; genitourinary infections; metabolic, endocrinologic, neurologic disorders; psychological disorders; and other pregnancy-related phenomena. Whereas women with mild to moderate nausea and vomiting of pregnancy usually have normal vital signs and an unremarkable physical examination, women with hyperemesis gravidarum typically display signs and symptoms of dehydration. Abdominal pain, fever, headache, hypertension, goiter, changes in bowel habits, and neurologic findings on examination indicate the need for further evaluation to rule out other clinical entities, because the differential diagnosis of nausea and vomiting of pregnancy is broad. Helicobacter pylori infection should be considered in patients who are unresponsive to treatment, keeping in mind that early pregnancy is not contraindication for endoscopic diagnosis (12).

Laboratory evaluation
Although hyperemesis gravidarum is a clinical diagnosis, laboratory abnormalities indicate the severity of disease and help exclude other potential diagnoses. Urine ketones, urine-specific gravity, and serum electrolytes should be ordered as initial tests to assess volume status. Additional blood tests (creatinine, blood urea nitrogen, calcium, complete blood count, amylase / lipase, and liver and thyroid function tests) may be required to exclude other disease processes but should be reserved for women in whom there is concern that hyperemesis gravidarum is not the correct diagnosis. Common laboratory derangements that may be encountered in severe cases of nausea and vomiting of pregnancy include elevated urine-specific gravity, ketonuria, hypokalemia, hypochloremic metabolic alkalosis, and ketosis (4). Hemoconcentration as a result of dehydration is often present. Abnormal liver function tests occur in up to 50% of hospitalized patients, with transaminitis being the most commonly noted abnormality. Alanine aminotransferase (ALT) levels are usually increased to a greater degree than aspartate aminotransferase (AST) levels. Typically, elevations in AST and ALT are 2 to3 times the upper limit of normal; levels greater than 1,000 U/mL are rare. A mild hyperbilirubinemia (<4 mg/dL) often accompanies the moderate transaminitis. Elevations in amylase and lipase are present in 10% to 15% of women because of excessive salivary gland production rather than pancreatitis (8).

In up to 60% of patients with hyperemesis gravidarum, levels of thyroid-stimulating hormone (TSH) may be diminished because of cross-reactivity between the α-subunit of hCG and TSH receptor (4),(8). Transient hyperthyroidism is usually self-limiting and clinically insignificant and does not require antithyroid therapy. Therefore, there is no need to routinely check thyroid function tests in women with presumed hyperemesis gravidarum, except if there is true concern for a diagnosis of Graves’ disease. Hyperemesis gravidarum is differentiated from other etiologies of hyperthyroidism by absence of ophthalmopathy, goiter and common signs and symptoms of hyperthyroidism (changes in bowel habits, tremor, and heat-intolerance). Although, hyperemesis gravidarum may be associated with mild elevations in free T4 levels and normal T3 levels, patients with true hyperthyroidism display obvious elevations in both T3 and T4 levels in addition to elevated TSH-receptor antibody levels.

Imaging
Obstetric ultrasound should be performed to exclude molar pregnancy and multiple gestations because these conditions are associated with nausea and vomiting of pregnancy and hyperemesis gravidarum. If liver or biliary disease is in the differential, a hepatic ultrasound is indicated.

Perinatal Outcomes

Maternal
Common maternal complications include dehydration, weight loss, and nutrient deficiencies. Wernicke’s encephalopathy caused by thiamine deficiency is a feared complication in which patients present with 3 to 4 weeks of persistent vomiting and with ataxia, nystagmus, and dementia (8). If left untreated, the condition can result in permanent neurologic dysfunction or death. It can be prevented with either oral or intravenous (IV) thiamine supplementation, particularly before infusion of dextrose-containing solutions. Other severe but rare maternal complications include peripheral neuropathy (as a result of vitamin B6, and B12 deficiencies), osmotic demyelination syndrome (because of over-rapid correction of hyponatremia), hepatic insufficiency, acute tubular necrosis, and complications caused by the mechanical stress of vomiting (esophageal rupture, Mallory-Weiss tears, and pneumothoraces) (8).

Neonatal
Mild to moderate nausea and vomiting of pregnancy is not associated with poor pregnancy outcomes. In fact, women with mild nausea and vomiting of pregnancy are at lower risk of miscarriage (13). In contrast, hyperemesis gravidarum with intractable vomiting, recurrent hospitalization, low pregnancy weight gain (<7 kg), and weight loss (>5% of pre-pregnancy weight) has been associated with low-birth weight and small-for-gestation-age infants and preterm delivery before 37 weeks’ gestation (14).

Management

Non-Pharmacologic Measures
The goals of management of hyperemesis include alleviation of nausea and vomiting, correction of dehydration and electrolyte abnormalities, and prevention of extreme maternal weight loss and complications. Given the risk of recurrence in a subsequent pregnancy, many women ask about preventive measures. There is evidence to suggest that risk of hyperemesis is decreased in women taking multivitamins at the time of conception of pregnancy (15). Initial management of nausea and vomiting of pregnancy begins with non-pharmacologic measures including dietary modifications, emotional support, and avoidance of triggers (16). Patient should be advised to eat small, frequent meals throughout the day and avoid caffeine, iron tablets, and spicy, odorous, and acidic foods. Bland low-fat, and dry foods are generally better tolerated, along with clear, carbonated liquids. High-protein diets, in contrast to carbohydrate-rich foods, have been shown to improve gastric dysrhythmias associated with nausea and vomiting of pregnancy. Behavioral therapy such as relaxation, hypnosis, and psychotherapy may help some patients (4). Emotional support and reassurance should be provided to all pregnant women with nausea and vomiting of pregnancy.

Ginger, which is recommended as a first-line measure for nausea and vomiting of pregnancy, stimulates GI-tract motility and has been shown to improve symptoms of nausea and vomiting (16). It does not appear to be associated with an increased risk of adverse effects in pregnancy but it may inhibit platelet function, and in theory could increase the risk of bleeding. Therefore, ginger should not be used in women predisposed to bleeding abnormalities (4). Acupressure wristbands have been studied as a treatment for nausea and vomiting of pregnancy, with inconsistent result (17). Some individual trials have shown a reduction in symptoms with P6 acupressure therapy, but in a recent Cochrane review, it was not found to be significantly more effective than placebo.

Pharmacologic Measures
For women with continued nausea and vomiting despite conservative measures and for those with hyperemesis gravidarum, multiple therapeutic agents are available. Pyridoxine has a favorable safety profile to improve nausea (16). Pyridoxine combined with doxylamine – an antihistamine – is a common first-line therapy (16). The combination was commercially available in the United States up until 1983, when it was pulled from the market because of litigation over congenital fetal malformations. Since then, however, multiple studies attest to the effectiveness and safety of oral pyridoxine-doxylamine in nausea and vomiting of pregnancy (16). Follow-up data on children with first-trimester exposure to pyridoxine-doxylamine for nausea and vomiting of pregnancy are reassuring. Pyridoxine-doxylamine is currently available in Canada and commonly used for nausea and vomiting of pregnancy (18).

Antihistamines, which directly inhibit histamine receptors and indirectly affect the vestibular system, decrease stimulation of the medullary vomiting center, thereby providing relief from nausea and vomiting of pregnancy (16). Dimenhydrinate, diphenhydramine, and meclizine are commonly used antihistamines for nausea and vomiting of pregnancy. Common adverse effects include sedation, dry mouth, and constipation. With a limited safety profile, dopamine antagonists are additional second-line therapeutic options for the treatment of nausea and vomiting of pregnancy and hyperemesis gravidarum. Because dopamine receptors in the stomach inhibit gastric motility, dopamine antagonists act as antiemetic agents during episodes of nausea and vomiting (16). Three main classes of dopamine receptor antagonists exist: phenothiazines (promethazine and prochlorperazine), benzamides (metoclopramide), and butyrophenones (droperidol). The antihistamine promethazine is the most commonly used dopamine antagonist and its fetal safety and maternal efficacy have been established in large groups of patients (17). Use caution when prescribing phenothiazines because dystonia and extrapyramidal symptoms can occur with prolonged use and high doses. Recently, the US Food and Drug Administration (FDA) updated drug labeling for use of prochlorperazine in the third trimester because of the possible risks of extrapyramidal effects in neonates (19).

Metoclopramide is a promotility agent commonly used to treat nausea and vomiting or pregnancy. Its efficacy may be similar to promethazine, although it has fewer adverse effects (such as sedation and dizziness) (20). Its safety profile in pregnancy has been well established. Drug-induced movement disorders are also of concern in long-term users of metoclopramide, and the FDA has issued a boxed warning concerning its use. Despite its proven efficacy in treating hyperemesis gravidarum, droperidol is another dopamine antagonist that is now less commonly used because of its safety concerns. It has been associated with QT prolongation and torsades de pointes, although these adverse effects occur at doses typically higher than those used to treat nausea and vomiting of pregnancy (21).

Ondansetron, a serotonin antagonist that blocks serotonin receptors in the medullary vomiting center and small bowel, is frequently used as an antiemetic during gestation (16). Although ondansetron is quite effective for nausea and vomiting of pregnancy, published experience is inadequate to consider it as first-line therapy. In addition to IV therapy, the antiemetic is also available in orally disintegrating tablets and for continuous infusion. FDA is currently performing a review of ondansetron and the risk of QT prolongation. Patients with underlying cardiac conditions or who take other QT-prolonging medications are likely to be most at risk (22). Methylprednisolone (16 mg IV or orally every 8 hours for 3 days followed by a steroid taper) deserves attention in refractory cases of hyperemesis gravidarum, although data on the benefit of corticosteroids are inconsistent (23). In light of a possible association between oral clefts and first-trimester exposure to glucocorticoids, methylprednisolone should not be used before 10 weeks’ gestation (23).

Tiered Approach to Medical Therapy for Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

Abbreviations: h, hour; IM, intramuscular; IV, intravenous; PO, by mouth; PR, per rectum.
a - Considered non-pharmacologic therapy.
b - Maximum dose, 400 mg/day, not to exceed 200 mg/day if patient is also taking doxylamine.
c - Taper over 2 weeks to lowest effective dose and limit total duration of use to 6 weeks if beneficial. Do not use before 10 weeks’ gestation because of possible increased risk of oral clefts.

Severe Hyperemesis Gravidarum

Women with severe hyperemesis gravidarum with intractable vomiting, nutritional deficiencies, or severe dehydration should be hospitalized for further management. Hospitalization is also indicated for women with moderate nausea and vomiting of pregnancy in whom outpatient management has failed (24). Inpatient treatment should include IV fluids, correction of electrolyte abnormalities (potassium, magnesium, calcium), and replenishment of vitamins (multivitamins, vitamin B6, thiamine) and folic acid. Nausea and vomiting can be treated with non-oral routes of antiemetic medications. Oral medications can be used in patients who can tolerate them. Hospitalized women should initially abide by a short period of bowel rest (nothing by mouth); followed by reintroduction of a diet that minimizes symptoms of nausea and vomiting (25). Home IV hydration therapy may benefit who need repeated hospitalization.

Enteral or total parental nutrition (TPN) should be reserved for women with persistent weight loss and recurrent hospitalization in spite of therapy. Obstetricians should work with nutritionists to determine the nutritional status and optimum method of alimentation. There are no data to suggest a difference in pregnancy outcomes with the various types of alimentary support, although serious complications, such as infection and thromboembolism are more likely with the parenteral route (25). A retrospective study reported a greater than 60% risk of maternal complications from peripherally inserted central catheters for TPN. Given the risk of maternal complications with TPN, enteral nutrition is the preferred route of alternative nutritional support. The multiple modalities of enteral nutrition include nasoenteric (nasogastric, nasoduodenal, or nasojejunal) tubes, percutaneous endoscopic gastrostomy tubes, and postpyloric feeding tubes. Although data suggest that these modalities are effective for providing nutrition, their use may be limited because of patient physical discomfort, risk of tube dislodgement and altered anatomy in pregnancy. Percutaneous endoscopic gastrostomy tubes also place patients at increased risk of nausea and vomiting caused by intragastric feeding. A small case series reported that surgical jejunostomy might be a safe and effective alternative mode of nutritional support in women with severe hyperemesis gravidarum (26).

Summary

Although the exact pathogenesis of hyperemesis gravidarum is unknown, its etiology is likely multifactorial. Abdominal pain, fever, headache, hypertension, goiter, changes in bowel habits, and neurologic findings indicate the need for further evaluation to rule out other clinical entities. Ginger stimulates GI-tract motility and has been shown to improve symptoms of nausea and vomiting. Multiple studies attest to the effectiveness and safety of oral pyridoxine-doxylamine in nausea and vomiting of pregnancy. Physicians must appreciate the magnitude of the condition given its widespread implications – economic costs, decreased quality of life, maternal psychological effects, and risks to mother and fetus. Current strategies include dietary modification, antiemetic therapy, and in certain situations, alimentary support. Antihistamines decrease stimulation of the medullary vomiting center, thereby providing relief from nausea and vomiting of pregnancy. Use caution when prescribing phenothiazines because dystonia and extrapyramidal symptoms can occur with prolonged use and high dose. Future strategies should include more randomized controlled trials therapies that are safe for both mother and fetus, and effective treatment to prevent hospitalization and offer alternatives for nutritional support.